RESUMO
The study introduced and evaluated learning paradigms for Maylandia callainos cichlids using a modified version of the rodent T-maze, filled with tank water (the "sunken" modification). Both male and female fish underwent training in two distinct conditioning paradigms. Firstly, simple operant conditioning involved placing a food reward in either the right or left compartment. Cichlids demonstrated the ability to purposefully find the bait within 6 days of training, with a persistent place preference lasting up to 6 days. Additionally, the learning dynamics varied with sex: female cichlids exhibited reduction in latency to visit the target compartment and consume the bait, along with a decrease in the number of errors 3 and 4 days earlier than males, respectively. Secondly, visually-cued operant conditioning was conducted, with a food reward exclusively placed in the yellow compartment, randomly positioned on the left or right side of the maze during each training session. Visual learning persisted for 10 days until reaction time improvement plateaued. Color preference disappeared after 4 consecutive check-ups, with no sex-related interference. For further validation of visually-cued operant conditioning paradigm, drugs MK-801 (dizocilpine) and caffeine, known to affect performance in learning tasks, were administered intraperitoneally. Chronic MK-801 (0.17â¯mg/kg) impaired maze learning, resulting in no color preference development. Conversely, caffeine administration enhanced test performance, increasing precision in fish. This developed paradigm offers a viable approach for studying learning and memory and presents an effective alternative to rodent-based drug screening tools, exhibiting good face and predictive validity.
Assuntos
Ciclídeos , Condicionamento Operante , Maleato de Dizocilpina , Aprendizagem em Labirinto , Animais , Ciclídeos/fisiologia , Masculino , Feminino , Condicionamento Operante/efeitos dos fármacos , Condicionamento Operante/fisiologia , Aprendizagem em Labirinto/efeitos dos fármacos , Aprendizagem em Labirinto/fisiologia , Maleato de Dizocilpina/farmacologia , Recompensa , Aprendizagem por Associação/fisiologia , Aprendizagem por Associação/efeitos dos fármacos , Antagonistas de Aminoácidos Excitatórios/farmacologia , Antagonistas de Aminoácidos Excitatórios/administração & dosagem , Sinais (Psicologia)RESUMO
This article explores the contribution of the double error dynamic asymptote computational associative learning model to understanding the role of mediated learning mechanisms in the generation of spurious associations, as those postulated to characterize schizophrenia. Three sets of simulations for mediated conditioning, mediated extinction, and a mediated enhancement of latent inhibition, a unique model prediction, are presented. For each set of simulations, a parameter that modulates the impact of associative memory retrieval and the dissipation of nonperceptual activated representations through the network was manipulated. The effect of this operation is analyzed and compared to ketamine-induced effects on associative memories and mediated learning. The model's potential to predict these effects and present a plausible error-correction associative mechanism is discussed in the context of animal models of schizophrenia. (PsycInfo Database Record (c) 2024 APA, all rights reserved).
Assuntos
Aprendizagem por Associação , Ketamina , Ketamina/farmacologia , Humanos , Aprendizagem por Associação/efeitos dos fármacos , Aprendizagem por Associação/fisiologia , Esquizofrenia/tratamento farmacológico , Simulação por Computador , Extinção Psicológica/efeitos dos fármacos , Animais , Condicionamento Clássico/efeitos dos fármacosRESUMO
An essential core function of one's cognitive flexibility is the use of acquired knowledge and skills to adapt to ongoing environmental changes. Animal models have highlighted the influence serotonin has on neuroplasticity. These effects have been predominantly demonstrated during emotional relearning which is theorized as a possible model for depression. However, translation of these mechanisms is in its infancy. To this end, we assessed changes in effective connectivity at rest and during associative learning as a proxy of neuroplastic changes in healthy volunteers. 76 participants underwent 6 weeks of emotional or non-emotional (re)learning (face-matching or Chinese character-German noun matching). During relearning participants either self-administered 10 mg/day of the selective serotonin reuptake inhibitor (SSRI) escitalopram or placebo in a double-blind design. Associative learning tasks, resting-state and structural images were recorded before and after both learning phases (day 1, 21 and 42). Escitalopram intake modulated relearning changes in a network encompassing the right insula, anterior cingulate cortex and right angular gyrus. Here, the process of relearning during SSRI intake showed a greater decrease in effective connectivity from the right insula to both the anterior cingulate cortex and right angular gyrus, with increases in the opposite direction when compared to placebo. In contrast, intrinsic connections and those at resting-state were only marginally affected by escitalopram. Further investigation of gray matter volume changes in these functionally active regions revealed no significant SSRI-induced structural changes. These findings indicate that the right insula plays a central role in the process of relearning and SSRIs further potentiate this effect. In sum, we demonstrated that SSRIs amplify learning-induced effective connections rather than affecting the intrinsic task connectivity or that of resting-state.
Assuntos
Aprendizagem por Associação , Conectoma , Córtex Insular , Rede Nervosa , Plasticidade Neuronal , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Adulto , Aprendizagem por Associação/efeitos dos fármacos , Aprendizagem por Associação/fisiologia , Citalopram/farmacologia , Feminino , Giro do Cíngulo/diagnóstico por imagem , Giro do Cíngulo/efeitos dos fármacos , Giro do Cíngulo/fisiologia , Humanos , Córtex Insular/diagnóstico por imagem , Córtex Insular/efeitos dos fármacos , Córtex Insular/fisiologia , Imageamento por Ressonância Magnética , Masculino , Rede Nervosa/diagnóstico por imagem , Rede Nervosa/efeitos dos fármacos , Rede Nervosa/fisiologia , Plasticidade Neuronal/efeitos dos fármacos , Plasticidade Neuronal/fisiologia , Lobo Parietal/diagnóstico por imagem , Lobo Parietal/efeitos dos fármacos , Lobo Parietal/fisiologia , Descanso , Inibidores Seletivos de Recaptação de Serotonina/administração & dosagem , Adulto JovemRESUMO
Alzheimer's disease (AD) is a profoundly debilitating neurodegenerative disorder characterized most notably by progressive cognitive decline, but also agitation and behavioral disturbances that are extremely disruptive to patient and caregiver. Current pharmacological treatments for these symptoms have limited efficacy and significant side effects. We have recently reported the discovery of Compound 24, an M4 positive allosteric modulator (PAM) that is potent, highly selective, and devoid of cholinergic-like side effects in rats. In order to further evaluate the translatability of the effects of compound 24 in primates, here we describe the effect of Compound 24 on three behavioral and cognition assays in rhesus monkeys, the stimulant induced motor activity (SIMA) assay, the object retrieval detour task (ORD), and the visuo-spatial paired-associates learning (vsPAL) task. As far as we know, this is the first such characterization of an M4 PAM in non-human primate. Compound 24 and the clinical standard olanzapine attenuated amphetamine induced hyperactivity to a similar degree. In addition, Compound 24 demonstrated procognitive effects in scopolamine-impaired ORD and vsPAL, and these effects were of similar magnitude to donepezil. These findings suggest that M4 PAMs may be beneficial to diseases such as Alzheimer's disease and schizophrenia, which are marked by behavioral disturbances as well as deficits in cognitive function.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/psicologia , Comportamento Animal/efeitos dos fármacos , Colinérgicos/farmacologia , Transtornos Cognitivos/tratamento farmacológico , Receptor Muscarínico M4/efeitos dos fármacos , Esquizofrenia/tratamento farmacológico , Psicologia do Esquizofrênico , Anfetamina/antagonistas & inibidores , Anfetamina/farmacologia , Animais , Aprendizagem por Associação/efeitos dos fármacos , Estimulantes do Sistema Nervoso Central , Colinérgicos/farmacocinética , Transtornos Cognitivos/psicologia , Hipercinese/induzido quimicamente , Hipercinese/prevenção & controle , Macaca mulatta , Masculino , Atividade Motora/efeitos dos fármacos , Olanzapina/farmacologia , Orientação/efeitos dos fármacosRESUMO
The rodent caudate-putamen is a large heterogeneous neural structure with distinct anatomical connections that differ in their control of learning processes. Previous research suggests that the anterior and posterior dorsomedial caudate-putamen (a- and p-dmCPu) differentially regulate associative learning with a non-contingent nicotine stimulus. The current study used bilateral NMDA-induced excitotoxic lesions to the a-dmCPu and p-dmCPu to determine the functional involvement of a-dmCPu and p-dmCPu in appetitive learning with contingent nicotine stimulus. Rats with a-dmCPu, p-dmCPu, or sham lesions were trained to lever-press for intravenous nicotine (0.03 mg/kg/inf) followed by access to sucrose 30 s later. After 1, 3, 9, and 20 nicotine-sucrose training sessions, appetitive learning in the form of a goal-tracking response was assessed using a non-contingent nicotine-alone test. All rats acquired nicotine self-administration and learned to retrieve sucrose from a receptacle at equal rates. However, rats with lesions to p-dmCPu demonstrated blunted learning of the nicotine-sucrose association. Our primary findings show that rats with lesions to p-dmCPu had a blunted goal-tracking response to a non-contingent nicotine administration after 20 consecutive days of nicotine-sucrose pairing. Our findings extend previous reports to a contingent model of nicotine self-administration and show that p-dmCPu is involved in associative learning with nicotine stimulus using a paradigm where rats voluntarily self-administer nicotine infusions that are paired with access to sucrose-a paradigm that closely resembles learning processes observed in humans.
Assuntos
Comportamento Apetitivo , Aprendizagem por Associação , Núcleo Caudado , Fármacos do Sistema Nervoso Central/administração & dosagem , Objetivos , Nicotina/administração & dosagem , Putamen , Animais , Comportamento Apetitivo/efeitos dos fármacos , Comportamento Apetitivo/fisiologia , Aprendizagem por Associação/efeitos dos fármacos , Aprendizagem por Associação/fisiologia , Núcleo Caudado/efeitos dos fármacos , Núcleo Caudado/fisiopatologia , Masculino , Putamen/efeitos dos fármacos , Putamen/fisiopatologia , Ratos , Ratos Sprague-Dawley , Autoadministração , Sacarose/administração & dosagem , Edulcorantes/administração & dosagemRESUMO
Renewal describes the recovery of an extinguished response if the contexts of extinction and recall differ, highlighting the context dependency of extinction. Studies demonstrated dopaminergic (DA) signalling to be important for context-related extinction learning with and without a fear component. In a previous study in humans, administration of the dopamine D2/D3 antagonist tiapride prior to extinction impaired extinction learning in a novel, but not a familiar context, without affecting renewal. In a further study, context processing during initial acquisition of associations was shown to be related to renewal. In this human fMRI study we investigated the potential role of DA signalling during this initial conditioning for the learning process and for renewal. While tiapride, administered prior to the start of learning, did not affect initial acquisition and renewal, extinction learning in a novel context was impaired, associated with reduced BOLD activation in vmPFC, left iFG and ACC - regions mediating response inhibition and selection from competing options using contextual information. Thus, different timepoints of administration of tiapride (before initial conditioning or extinction) had largely similar effects upon extinction and renewal. In addition, retrieval of previously acquired associations was impaired, pointing towards weaker association forming during acquisition. Conceivably, effects of the DA blockade are associated with the challenge present in the respective task rather than the administration timepoint: the cognitive flexibility required for forming a new inhibitory association that includes a novel element clearly requires DA processing, while initial forming of associations, or of inhibitory associations without a new element, apparently rely less on the proper function of the DA system.
Assuntos
Aprendizagem por Associação/efeitos dos fármacos , Antagonistas de Dopamina/farmacologia , Extinção Psicológica/efeitos dos fármacos , Reconhecimento Psicológico/efeitos dos fármacos , Cloridrato de Tiaprida/farmacologia , Adolescente , Adulto , Aprendizagem por Associação/fisiologia , Extinção Psicológica/fisiologia , Feminino , Neuroimagem Funcional , Giro do Cíngulo/efeitos dos fármacos , Giro do Cíngulo/fisiologia , Humanos , Aprendizagem/efeitos dos fármacos , Aprendizagem/fisiologia , Imageamento por Ressonância Magnética , Masculino , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/fisiologia , Reconhecimento Psicológico/fisiologia , Adulto JovemRESUMO
There is high clinical interest in improving the pharmacological treatment of individuals with Major Depressive Disorder (MDD). This neuropsychiatric disorder continues to cause significant morbidity and mortality worldwide, where existing pharmaceutical treatments such as selective serotonin reuptake inhibitors often have limited efficacy. In a recent publication, we demonstrated an antidepressant-like role for the acetylcholinesterase inhibitor (AChEI) donepezil in the C57BL/6J mouse forced swim test (FST). Those data added to a limited literature in rodents and human subjects which suggests AChEIs have antidepressant properties, but added the novel finding that donepezil only showed antidepressant-like properties at lower doses (0.02, 0.2 mg/kg). At a high dose (2.0 mg/kg), donepezil tended to promote depression-like behavior, suggesting a u-shaped dose-response curve for FST immobility. Here we investigate the effects of three other AChEIs with varying molecular structures: galantamine, physostigmine, and rivastigmine, to test whether they also exhibit antidepressant-like effects in the FST. We find that these drugs do exhibit therapeutic-like effects at low but not high doses, albeit at lower doses for physostigmine. Further, we find that their antidepressant-like effects are not mediated by generalized hyperactivity in the novel open field test, and are also not accompanied by anxiolytic-like properties. These data further support the hypothesis that acetylcholine has a u-shaped dose-response relationship with immobility in the C57BL/6J mouse FST, and provide a rationale for more thoroughly investigating whether reversible AChEIs as a class can be repurposed for the treatment of MDD in human subjects.
Assuntos
Antidepressivos/farmacologia , Comportamento Animal/efeitos dos fármacos , Inibidores da Colinesterase/farmacologia , Atividade Motora/efeitos dos fármacos , Animais , Aprendizagem por Associação/efeitos dos fármacos , Inibidores da Colinesterase/administração & dosagem , Donepezila/farmacologia , Relação Dose-Resposta a Droga , Reposicionamento de Medicamentos , Galantamina/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fisostigmina/farmacologia , Rivastigmina/farmacologia , NataçãoRESUMO
Fetal alcohol spectrum disorder (FASD) is the most common cause of birth defects. The severe variations are in fetal alcohol syndrome (FAS) but the most frequent cases are alcohol-related neurodevelopmental disorder (ARND), which is of a difficult diagnosis. ARND characteristics include impaired social behavior, anxiety and depression prevalence, cognitive deficits, and an increased chance for drug addiction. Here, we aimed to test whether early alcohol exposure leads to later alcohol preference. We hypothesize that early alcohol exposure increases the reinforcing effects on later experiences, raising the chance of addiction in adult life. Lately, the zebrafish has been a valuable model on alcohol research, allowing embryonic exposure and the study of the ontogenetic effects. For this, embryos were exposed to three different alcohol treatments: 0.0%, 0.25% and 0.5%, for 2 hr, at 24-hr post-fertilization. Then we evaluated the effects of embryonic alcohol exposure on conditioned place preference in two developmental stage: fry (10 days post-fertilization (dpf)) and young (90 dpf) zebrafish. Results show that control fish presented alcohol associative learning, which means, changes in place preference due to alcohol exposure, at both ontogenetic phases. However, zebrafish exposed to 0.25 and 0.5% alcohol during embryogenesis did not show conditioning response at any evaluated stage. These results suggest perception and cognitive deficits due to embryonic alcohol exposure that can alter alcohol responsiveness throughout a lifetime. Although low alcohol doses do not provoke malformation, it has been shown to induce several neurological and behavioral changes that are termed as Alcohol-Related Neurodevelopmental Disorders. These results may contribute to future investigations on how embryonic exposure affects the neurocircuitry related to perception and associative learning processing.
Assuntos
Comportamento de Procura de Droga/efeitos dos fármacos , Etanol/farmacologia , Transtornos do Espectro Alcoólico Fetal/psicologia , Peixe-Zebra , Envelhecimento , Consumo de Bebidas Alcoólicas , Animais , Aprendizagem por Associação/efeitos dos fármacos , Condicionamento Operante , Relação Dose-Resposta a Droga , Embrião não Mamífero , Desenvolvimento Embrionário/efeitos dos fármacos , Feminino , MasculinoRESUMO
Animal studies using selective serotonin reuptake inhibitors (SSRIs) and learning paradigms have demonstrated that serotonin is important for flexibility in executive functions and learning. SSRIs might facilitate relearning through neuroplastic processes and thus exert their clinical effects in psychiatric diseases where cognitive functioning is affected. However, translation of these mechanisms to humans is missing. In this randomized placebo-controlled trial, we assessed functional brain activation during learning and memory retrieval in healthy volunteers performing associative learning tasks aiming to translate facilitated relearning by SSRIs. To this extent, seventy-six participants underwent three MRI scanning sessions: (1) at baseline, (2) after three weeks of daily associative learning and subsequent retrieval (face-matching or Chinese character-noun matching) and (3) after three weeks of relearning under escitalopram (10 mg/day) or placebo. Associative learning and retrieval tasks were performed during each functional MRI (fMRI) session. Statistical modeling was done using a repeated-measures ANOVA, to test for content-by-treatment-by-time interaction effects. During the learning task, a significant substance-by-time interaction was found in the right insula showing a greater deactivation in the SSRI cohort after 21 days of relearning compared to the learning phase. In the retrieval task, there was a significant content-by-time interaction in the left angular gyrus (AG) with an increased activation in face-matching compared to Chinese-character matching for both learning and relearning phases. A further substance-by-time interaction was found in task performance after 21 days of relearning, indicating a greater decrease of performance in the placebo group. Our findings that escitalopram modulate insula activation demonstrates successful translation of relearning as a mechanism of SSRIs in human. Furthermore, we show that the left AG is an active component of correct memory retrieval, which coincides with previous literature. We extend the function of this region by demonstrating its activation is not only stimulus dependent but also time constrained. Finally, we were able to show that escitalopram aids in relearning, irrespective of content.
Assuntos
Aprendizagem por Associação/efeitos dos fármacos , Córtex Cerebral , Citalopram/farmacologia , Rememoração Mental/efeitos dos fármacos , Plasticidade Neuronal/efeitos dos fármacos , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Adulto , Mapeamento Encefálico , Córtex Cerebral/diagnóstico por imagem , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/fisiologia , Citalopram/administração & dosagem , Método Duplo-Cego , Feminino , Humanos , Estudos Longitudinais , Imageamento por Ressonância Magnética , Masculino , Lobo Parietal/diagnóstico por imagem , Lobo Parietal/efeitos dos fármacos , Lobo Parietal/fisiologia , Reconhecimento Visual de Modelos/fisiologia , Inibidores Seletivos de Recaptação de Serotonina/administração & dosagem , Adulto JovemRESUMO
Four experiments examined the effects of a dangerous context and a systemic epinephrine injection on sensory preconditioning in rats. In each experiment, rats were exposed to presentations of a tone and light in stage 1, light-shock pairings in stage 2, and test presentations of the tone alone and light alone in stage 3. Presentations of the tone and light in stage 1 occurred in either a safe or a previously shocked context, and/or under a systemic injection of epinephrine. Experiment 1 showed that a trace interval of 20 sec between presentations of the tone and light produced sensory preconditioning of the tone in a previously shocked context but not in a safe context, while experiment 2 provided evidence that this trace preconditioning was associative, due to the formation of a tone-light association. Experiment 3 showed that, in a safe context, exposure to the trace protocol under the influence of an epinephrine injection also produced sensory preconditioning of the tone, while experiment 4 provided evidence that a shocked context and an epinephrine injection have additive effects on trace preconditioning. These findings are discussed in relation to theories of trace conditioning. They suggest that the release of epinephrine by danger enhances attention and/or working memory processes, and thereby associative formation across a trace interval.
Assuntos
Aprendizagem por Associação/efeitos dos fármacos , Aprendizagem por Associação/fisiologia , Comportamento Animal/fisiologia , Condicionamento Psicológico/efeitos dos fármacos , Condicionamento Psicológico/fisiologia , Epinefrina/farmacologia , Epinefrina/fisiologia , Medo/fisiologia , Animais , Percepção Auditiva/fisiologia , Comportamento Animal/efeitos dos fármacos , Eletrochoque , Epinefrina/administração & dosagem , Medo/efeitos dos fármacos , Masculino , Ratos , Ratos Sprague-Dawley , Segurança , Percepção Visual/fisiologiaRESUMO
Impaired cognitive flexibility represents a widespread symptom in psychiatric disorders, including major depressive disorder (MDD), a disease, characterized by an imbalance of neurotransmitter concentrations. While memory formation is mostly associated with glutamate, also gamma-Aminobutyric acid (GABA) and serotonin show attributions in a complex interplay between neurotransmitter systems. Treatment with selective serotonin reuptake inhibitors (SSRIs) does not solely affect the serotonergic system but shows downstream effects on GABA- and glutamatergic neurotransmission, potentially helping to restore cognitive function via neuroplastic effects. Hence, this study aims to elaborate the effects of associative relearning and SSRI treatment on GABAergic and glutamatergic function within and between five brain regions using magnetic resonance spectroscopy imaging (MRSI). In this study, healthy subjects were randomized into four groups which underwent three weeks of an associative relearning paradigm, with or without emotional connotation, under SSRI (10mg escitalopram) or placebo administration. MRSI measurements, using a spiral-encoded, 3D-GABA-edited MEGA-LASER sequence at 3T, were performed on the first and last day of relearning. Mean GABA+/tCr (GABA+ = GABA + macromolecules; tCr = total creatine) and Glx/tCr (Glx = glutamate + glutamine) ratios were quantified in a ROI-based approach for the hippocampus, insula, putamen, pallidum and thalamus, using LCModel. A total of 66 subjects ((37 female, mean age ± SD = 25.4±4.7) for Glx/tCr and 58 subjects (32 female, mean age ± SD = 25.1±4.7) for GABA+/tCr were included in the final analysis. A significant measurement by region and treatment (SSRI vs placebo) interaction on Glx/tCr ratios was found (pcor=0.017), with post hoc tests confirming differential effects on hippocampus and thalamus (pcor=0.046). Moreover, treatment by time comparison, for each ROI independently, showed a reduction of hippocampal Glx/tCr ratios after SSRI treatment (puncor=0.033). No significant treatment effects on GABA+/tCr ratios or effects of relearning condition on any neurotransmitter ratio could be found. Here, we showed a significant SSRI- and relearning-driven interaction effect of hippocampal and thalamic Glx/tCr levels, suggesting differential behavior based on different serotonin transporter and receptor densities. Moreover, an indication for Glx/tCr adaptions in the hippocampus after three weeks of SSRI treatment could be revealed. Our findings are in line with animal studies reporting glutamate adaptions in the hippocampus following chronic SSRI intake. Due to the complex interplay of serotonin and hippocampal function, involving multiple serotonin receptor subtypes on glutamatergic cells and GABAergic interneurons, the interpretation of underlying neurobiological actions remains challenging.
Assuntos
Aprendizagem por Associação/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Ácido Glutâmico/metabolismo , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Ácido gama-Aminobutírico/metabolismo , Adulto , Aprendizagem por Associação/fisiologia , Encéfalo/diagnóstico por imagem , Método Duplo-Cego , Feminino , Humanos , Estudos Longitudinais , Imageamento por Ressonância Magnética/métodos , Espectroscopia de Ressonância Magnética/métodos , Masculino , Estimulação Luminosa/métodos , Adulto JovemRESUMO
This paper introduces a new construct, the 'pivotal mental state', which is defined as a hyper-plastic state aiding rapid and deep learning that can mediate psychological transformation. We believe this new construct bears relevance to a broad range of psychological and psychiatric phenomena. We argue that pivotal mental states serve an important evolutionary function, that is, to aid psychological transformation when actual or perceived environmental pressures demand this. We cite evidence that chronic stress and neurotic traits are primers for a pivotal mental state, whereas acute stress can be a trigger. Inspired by research with serotonin 2A receptor agonist psychedelics, we highlight how activity at this particular receptor can robustly and reliably induce pivotal mental states, but we argue that the capacity for pivotal mental states is an inherent property of the human brain itself. Moreover, we hypothesize that serotonergic psychedelics hijack a system that has evolved to mediate rapid and deep learning when its need is sensed. We cite a breadth of evidences linking stress via a variety of inducers, with an upregulated serotonin 2A receptor system (e.g. upregulated availability of and/or binding to the receptor) and acute stress with 5-HT release, which we argue can activate this primed system to induce a pivotal mental state. The pivotal mental state model is multi-level, linking a specific molecular gateway (increased serotonin 2A receptor signaling) with the inception of a hyper-plastic brain and mind state, enhanced rate of associative learning and the potential mediation of a psychological transformation.
Assuntos
Alucinógenos/farmacologia , Misticismo , Plasticidade Neuronal , Transtornos Psicóticos , Receptor 5-HT2A de Serotonina/metabolismo , Agonistas do Receptor 5-HT2 de Serotonina/farmacologia , Estresse Psicológico , Aspirações Psicológicas , Aprendizagem por Associação/efeitos dos fármacos , Aprendizagem por Associação/fisiologia , Humanos , Atenção Plena/métodos , Plasticidade Neuronal/efeitos dos fármacos , Plasticidade Neuronal/fisiologia , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Estresse Fisiológico/efeitos dos fármacos , Estresse Fisiológico/fisiologia , Estresse Psicológico/metabolismo , Estresse Psicológico/psicologia , Estresse Psicológico/terapiaRESUMO
Navigating the physical world requires learning probabilistic associations between sensory events and their change in time (volatility). Bayesian accounts of this learning process rest on hierarchical prediction errors (PEs) that are weighted by estimates of uncertainty (or its inverse, precision). In a previous fMRI study we found that low-level precision-weighted PEs about visual outcomes (that update beliefs about associations) activated the putative dopaminergic midbrain; by contrast, precision-weighted PEs about cue-outcome associations (that update beliefs about volatility) activated the cholinergic basal forebrain. These findings suggested selective dopaminergic and cholinergic influences on precision-weighted PEs at different hierarchical levels. Here, we tested this hypothesis, repeating our fMRI study under pharmacological manipulations in healthy participants. Specifically, we performed two pharmacological fMRI studies with a between-subject double-blind placebo-controlled design: study 1 used antagonists of dopaminergic (amisulpride) and muscarinic (biperiden) receptors, study 2 used enhancing drugs of dopaminergic (levodopa) and cholinergic (galantamine) modulation. Pooled across all pharmacological conditions of study 1 and study 2, respectively, we found that low-level precision-weighted PEs activated the midbrain and high-level precision-weighted PEs the basal forebrain as in our previous study. However, we found pharmacological effects on brain activity associated with these computational quantities only when splitting the precision-weighted PEs into their PE and precision components: in a brainstem region putatively containing cholinergic (pedunculopontine and laterodorsal tegmental) nuclei, biperiden (compared to placebo) enhanced low-level PE responses and attenuated high-level PE activity, while amisulpride reduced high-level PE responses. Additionally, in the putative dopaminergic midbrain, galantamine compared to placebo enhanced low-level PE responses (in a body-weight dependent manner) and amisulpride enhanced high-level precision activity. Task behaviour was not affected by any of the drugs. These results do not support our hypothesis of a clear-cut dichotomy between different hierarchical inference levels and neurotransmitter systems, but suggest a more complex interaction between these neuromodulatory systems and hierarchical Bayesian quantities. However, our present results may have been affected by confounds inherent to pharmacological fMRI. We discuss these confounds and outline improved experimental tests for the future.
Assuntos
Acetilcolina/metabolismo , Aprendizagem por Associação/fisiologia , Encéfalo/fisiologia , Dopamina/metabolismo , Aprendizagem por Associação/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Mapeamento Encefálico/métodos , Colinérgicos/farmacologia , Dopaminérgicos/farmacologia , Método Duplo-Cego , Humanos , Imageamento por Ressonância Magnética/métodos , Masculino , Incerteza , Adulto JovemRESUMO
Dietary nitrate lowers blood pressure and improves athletic performance in humans, yet data supporting observations that it may increase cerebral blood flow and improve cognitive performance are mixed. We tested the hypothesis that nitrate and nitrite treatment would improve indicators of learning and cognitive performance in a zebrafish (Danio rerio) model. We utilized targeted and untargeted liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis to examine the extent to which treatment resulted in changes in nitrate or nitrite concentrations in the brain and altered the brain metabolome. Fish were exposed to sodium nitrate (606.9 mg/L), sodium nitrite (19.5 mg/L), or control water for 2-4 weeks and free swim, startle response, and shuttle box assays were performed. Nitrate and nitrite treatment did not change fish weight, length, predator avoidance, or distance and velocity traveled in an unstressed environment. Nitrate- and nitrite-treated fish initially experienced more negative reinforcement and increased time to decision in the shuttle box assay, which is consistent with a decrease in associative learning or executive function however, over multiple trials, all treatment groups demonstrated behaviors associated with learning. Nitrate and nitrite treatment was associated with mild anxiogenic-like behavior but did not alter epinephrine, norepinephrine or dopamine levels. Targeted metabolomics analysis revealed no significant increase in brain nitrate or nitrite concentrations with treatment. Untargeted metabolomics analysis found 47 metabolites whose abundance was significantly altered in the brain with nitrate and nitrite treatment. Overall, the depletion in brain metabolites is plausibly associated with the regulation of neuronal activity including statistically significant reductions in the inhibitory neurotransmitter γ-aminobutyric acid (GABA; 18-19%), and its precursor, glutamine (17-22%). Nitrate treatment caused significant depletion in the brain concentration of fatty acids including linoleic acid (LA) by 50% and arachidonic acid (ARA) by 80%; nitrite treatment caused depletion of LA by ~90% and ARA by 60%, change which could alter the function of dopaminergic neurons and affect behavior. Nitrate and nitrite treatment did not adversely affect multiple parameters of zebrafish health. It is plausible that indirect NO-mediated mechanisms may be responsible for the nitrate and nitrite-mediated effects on the brain metabolome and behavior in zebrafish.
Assuntos
Aprendizagem por Associação/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Função Executiva/efeitos dos fármacos , Metaboloma/efeitos dos fármacos , Nitratos/farmacologia , Nitrito de Sódio/farmacologia , Animais , Ansiedade/induzido quimicamente , Ansiedade/psicologia , Ácido Araquidônico/antagonistas & inibidores , Ácido Araquidônico/metabolismo , Comportamento Animal/efeitos dos fármacos , Tamanho Corporal/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Encéfalo/metabolismo , Dopamina/metabolismo , Epinefrina/metabolismo , Feminino , Glutamina/metabolismo , Ácido Linoleico/antagonistas & inibidores , Ácido Linoleico/metabolismo , Masculino , Metaboloma/fisiologia , Norepinefrina/metabolismo , Reflexo de Sobressalto/efeitos dos fármacos , Reforço Psicológico , Peixe-Zebra/metabolismo , Ácido gama-Aminobutírico/metabolismoRESUMO
The entomopathogenic fungus Beauveria bassiana is a widely used biopesticide that is considered as an effective alternative to classical agrochemicals. B. bassiana is thought to be safe for pollinators although little is known about its side-effects on pollinators' behaviour and cognition. Here, we focused on honey bees and used the proboscis extension response (PER) protocol to assess whether B. bassiana affects individual sucrose responsiveness, non-associative and associative olfactory learning and memory. Fungus-treated bees displayed an enhanced sucrose responsiveness, which could not be explained by metabolic alterations. Strikingly, exposed bees were twice as inconsistent as controls in response to sucrose, showing PER to lower but not to higher sucrose concentrations. Exposed bees habituated less to sucrose and had a better acquisition performance in the conditioning phase than controls. Further, neither mid- nor long-term memory were affected by the fungus. As sucrose responsiveness is the main determinant of division of foraging labour, these changes might unsettle the numerical ratio between the sub-castes of foragers leading to suboptimal foraging. Although the use of biocontrol strategies should be preferred over chemical pesticides, careful assessment of their side-effects is crucial before claiming that they are safe for pollinators.
Assuntos
Aprendizagem por Associação/efeitos dos fármacos , Abelhas/crescimento & desenvolvimento , Memória/efeitos dos fármacos , Praguicidas/farmacologia , Olfato/efeitos dos fármacos , Sacarose/farmacologia , Edulcorantes/farmacologia , Animais , Abelhas/efeitos dos fármacos , Comportamento Animal , Condicionamento ClássicoRESUMO
Previous studies suggest that trace conditioning depends on the anterior cingulate cortex (ACC). To examine the role of ACC in trace fear conditioning further, 48 rats were surgically prepared for infusion with saline or 62.5 or 125 µg/side muscimol to inactivate ACC reversibly prior to conditioning. A noise stimulus was followed by a 1 mA footshock, with or without a 10-second trace interval between these events in a conditioned suppression procedure. The trace-conditioned groups (10 seconds) showed less test suppression than the control-conditioned groups (0 seconds). Counter to prediction, there was no effect of muscimol infusion on suppression to the noise stimulus in the 10-second trace groups.
Assuntos
Aprendizagem por Associação/efeitos dos fármacos , Comportamento Animal/efeitos dos fármacos , Condicionamento Clássico/efeitos dos fármacos , Medo/efeitos dos fármacos , Agonistas GABAérgicos/farmacologia , Giro do Cíngulo/efeitos dos fármacos , Muscimol/farmacologia , Animais , Agonistas GABAérgicos/administração & dosagem , Masculino , Muscimol/administração & dosagem , Ratos , Ratos WistarRESUMO
BACKGROUND: Epidemiological studies indicate a rise in the combined consumption of caffeinated and alcoholic beverages, which can lead to increased risk of alcoholic-beverage overconsumption. However, the effects of the combination of caffeine and ethanol in animal models related to aspects of drug addiction are still underexplored. AIMS: To characterize the pharmacological interaction between caffeine and ethanol and establish if caffeine can affect the ability of ethanol (2 g/kg) to elicit conditioned place preference and conditioned place aversion, we administered caffeine (3 or 15 mg/kg) to male CD-1 mice before saline or ethanol. Moreover, we determined if these doses of caffeine could affect ethanol (2 g/kg) elicited extracellular signal-regulated kinase phosphorylation in brain areas, nucleus accumbens, bed nucleus of stria terminalis, central nucleus of the amygdala, and basolateral amygdala, previously associated with this type of associative learning. RESULTS: In the place-conditioning paradigm, caffeine did not have an effect on its own, whereas ethanol elicited significant conditioned-place preference and conditioned-place aversion. Caffeine (15 mg/kg) significantly prevented the acquisition of ethanol-elicited conditioned-place preference and, at both doses, also prevented the acquisition of ethanol-elicited conditioned-place aversion. Moreover, both doses of caffeine also prevented ethanol-elicited extracellular signal-regulated kinase phosphorylation expression in all brain areas examined. CONCLUSIONS: The present data indicate a functional antagonistic action of caffeine and ethanol on associative learning and extracellular signal-regulated kinase phosphorylation after an acute interaction. These results could provide exciting grounds for further studies, also in a translational perspective, of their pharmacological interaction modulating other processes involved in drug consumption and addiction.
Assuntos
Tonsila do Cerebelo/efeitos dos fármacos , Aprendizagem por Associação/efeitos dos fármacos , Aprendizagem da Esquiva/efeitos dos fármacos , Cafeína/farmacologia , Depressores do Sistema Nervoso Central/farmacologia , Estimulantes do Sistema Nervoso Central/farmacologia , Comportamento de Escolha/efeitos dos fármacos , Condicionamento Clássico/efeitos dos fármacos , Etanol/farmacologia , MAP Quinases Reguladas por Sinal Extracelular/efeitos dos fármacos , Animais , Comportamento Animal/efeitos dos fármacos , Cafeína/administração & dosagem , Depressores do Sistema Nervoso Central/administração & dosagem , Estimulantes do Sistema Nervoso Central/administração & dosagem , Interações Medicamentosas , Etanol/administração & dosagem , Masculino , Camundongos , Núcleo Accumbens/efeitos dos fármacos , Fosforilação/efeitos dos fármacos , Núcleos Septais/efeitos dos fármacos , Percepção Espacial/efeitos dos fármacosRESUMO
Cannabinoids are notorious and profound modulators of behavioral state. In the brain, endocannabinoids act via Type 1-cannabinoid receptors (CB1) to modulate synaptic transmission and mediate multiple forms of synaptic plasticity. CB1 knockout (CB1KO) mice display a range of behavioral phenotypes, in particular hypoactivity and various deficits in learning and memory, including cerebellum-dependent delay eyeblink conditioning. Here we find that the apparent effects of CB1 deletion on cerebellar learning are not due to direct effects on CB1-dependent plasticity, but rather, arise as a secondary consequence of altered behavioral state. Hypoactivity of CB1KO mice accounts for their impaired eyeblink conditioning across both animals and trials. Moreover, learning in these mutants is rescued by walking on a motorized treadmill during training. Finally, cerebellar granule-cell-specific CB1KOs exhibit normal eyeblink conditioning, and both global and granule-cell-specific CB1KOs display normal cerebellum-dependent locomotor coordination and learning. These findings highlight the modulation of behavioral state as a powerful independent means through which individual genes contribute to complex behaviors.
Assuntos
Aprendizagem por Associação/efeitos dos fármacos , Canabinoides/farmacologia , Cerebelo/fisiologia , Receptor CB1 de Canabinoide/metabolismo , Animais , Cerebelo/efeitos dos fármacos , Feminino , Masculino , Camundongos , Camundongos KnockoutRESUMO
The T-type calcium channel blocker, Z944, has been used as a pharmacological tool to assess T-type calcium channel function and examined for use as an anti-epileptic. As Z944 affects fear learning and memory in a rodent model of absence epilepsy, it is important to determine the effect of Z944 on learning and memory in a non-disease outbred rodent strain. This study examined the dose-dependent effects (5 mg/kg, 10 mg/kg, i.p.) of acute systemic treatment with Z944 on the learning and memory of fear conditioning and extinction in male Wistar rats. Z944 administered prior to the acquisition of fear conditioning significantly increased freezing prior to acquisition and extinction, during acquisition, and impaired recall of fear memory 24 h later. These findings suggest that T-type calcium channel activity may be required during associative learning for intact long-term memory. Enhanced fear behaviour observed prior to acquisition and extinction, and during acquisition could reflect an increase in anxiety, however, further testing is needed to determine the effect of Z944 on anxiety during fear conditioning and extinction. The use of Z944 for therapeutic purposes should consider the potential effects of Z944 on learning and memory in clinical populations.
Assuntos
Aprendizagem por Associação/efeitos dos fármacos , Bloqueadores dos Canais de Cálcio/farmacologia , Canais de Cálcio Tipo T/metabolismo , Condicionamento Psicológico/efeitos dos fármacos , Medo/efeitos dos fármacos , Animais , Relação Dose-Resposta a Droga , Medo/fisiologia , Masculino , Rememoração Mental/efeitos dos fármacos , Piperidinas/farmacologia , Ratos , Ratos WistarRESUMO
BACKGROUND: Psychotic disorders are characterized by prominent deficits in associative learning and memory for which there are currently no effective treatments. Functional magnetic resonance imaging (fMRI) studies in psychotic disorders have identified deficits in fronto-temporal activation during associative learning and memory. The underlying pathology of these findings remains unclear. Postmortem data have suggested these deficits may be related to loss of muscarinic M1 receptor mediated signaling. This is supported by an in-vivo study showing improvements in these symptoms after treatment with the experimental M1/4 receptor agonist xanomeline. The current study tests whether reported deficits in fronto-temporal activation could be mediated by loss of M1 receptor signaling in psychotic disorders. METHODS: Twenty-six medication-free subjects diagnosed with a psychotic disorder and 29 age-, gender-, and IQ-matched healthy controls underwent two functional magnetic resonance imaging (fMRI) sessions, one under placebo and one under selective M1 antagonist biperiden, while performing the paired associated learning task. M1 binding potentials (BPND) were measured in the dorsolateral prefrontal cortex (DLPFC) and hippocampus using 123I-IDEX single photon emission computed tomography. RESULTS: In the subjects with psychotic disorders DLPFC hypoactivation was only found in the memory phase of the task. In both learning and memory phases of the task, M1 antagonism by biperiden elicited significantly greater hyperactivation of the parahippocampal gyrus and superior temporal gyrus in subjects with a psychotic disorders compared to controls. Greater hyperactivation of these areas after biperiden was associated with greater hippocampal M1 receptor binding during learning, with no association found with M1 receptor binding in the DLPFC. M1 receptor binding in the DLPFC was related to greater functional sensitivity to biperiden of the cingulate gyrus during the memory phase. CONCLUSION: The current study is the first to show differences in M1 receptor mediated functional sensitivity between subjects with a psychotic disorder and controls during a paired associate learning and memory task. Results point to subjects with psychotic disorders having a loss of M1 receptor reserve in temporal-limbic areas.